Abstract
Background
Ocular administration of mydriatics, phenylephrine and cyclopentolate, is commonly used in preterm infants for retinopathy of prematurity eye examinations. Although the diagnostic mydriatic eye drops are considered safe for worldwide use in preterm infants, this thesis aims to investigate how safety could be improved whilst maintaining efficacy. Minimising medication related risk is important for this cohort because approximately 90% of infants screened for retinopathy of prematurity will not require medical intervention. Therefore, when considering the risk benefit profile, the risk of adverse events associated with mydriatics needs to be less than the benefit of having the eye examination.
Aim
To investigate if microdrop administration of phenylephrine and cyclopentolate is effective at providing sufficient pupil dilation in preterm infants for retinopathy of prematurity eye examinations.
Methods
A systematic review was performed and included all clinical trials, irrespective of methodology, which investigated efficacy and safety of any mydriatic regimen used in preterm infants. Case reports of adverse drug events associated with mydriatics when used in preterm infants were also included.
A survey of neonatal nurses was performed to gather evidence for the range of concentration, drop volume, and frequency of administration of mydriatic regimens used in preterm infants for retinopathy of prematurity eye examinations.
A randomised controlled pilot trial investigating the efficacy and safety of phenylephrine 1% and cyclopentolate 0.2% microdrop (n=9), and phenylephrine 0.5% and cyclopentolate 0.1% microdrop (n=8) was carried out in preterm infants for their retinopathy of prematurity eye examinations. Data collected in the pilot study was used to inform the methodology for the multicentre randomised controlled trial, and to secure funding for the trial.
A multicentre non-inferiority randomised controlled trial (The Little Eye Drop Study) investigated the efficacy and safety of phenylephrine 1% and cyclopentolate 0.2% microdrops (n=74), and phenylephrine 0.5%, and cyclopentolate 0.1% microdrops (n=76) was carried out in preterm infants for their retinopathy of prematurity eye examinations.
Main Findings
This thesis identified and discovered new information on the following:
1. Published evidence used to inform mydriatic regimen in clinical guidelines are underpowered and are often associated with a high level of bias.
2. There are multiple mydriatic regimens in use across Aotearoa New Zealand and Australia. Some neonatal units in these countries are using equivalent to, or more than, an adult dose.
3. Pupil dilation measurements in preterm infants is challenging. A suitable method for measuring the pupil is by photographing the eye with a red reflex then importing the photo into software for measurement.
4. The appropriate outcome measure of whether mydriatics sufficiently dilate pupils is if the ophthalmologist can perform the retinopathy of prematurity eye examination.
5. Phenylephrine 0.5% and cyclopentolate 0.1% (very low dose) in a microdrop volume is effective at sufficiently dilating the pupil for retinopathy of prematurity eye examination in preterm infants who have up to Grade 2 retinopathy of prematurity.
6. Both mydriatic regimens evaluated in the multicentre non-inferiority randomised controlled trial were effective at pupil dilation in infants with dark pigmented iris.
7. Phenylephrine 1% and cyclopentolate 0.2% (low dose) in a microdrop volume are more likely to require single dose administration, be more likely to have an eye examination rated as easy by the ophthalmologist, and more likely to have a pupil dilation above 5 mm.
8. Phenylephrine 0.5% and cyclopentolate 0.1% (very low dose) in a microdrop volume are more likely to have an eye examination rated as difficult by the ophthalmologist, more likely to require two administrations, and less likely to provide pupil dilation above 5 mm.
9. In Māori preterm infants, phenylephrine 1% and cyclopentolate 0.2% (low dose), and phenylephrine 0.5% and cyclopentolate 0.1% (very low dose), in a microdrop volume is likely to be effective at sufficiently dilating the pupil for retinopathy of prematurity eye examination in preterm infants who have up to Grade 2 retinopathy of prematurity.
10. There are no commercially available devices that have been tested in preterm infants to administer a microdose volume of mydriatics.
Conclusion
Microdrop administration of phenylephrine 1% with cyclopentolate 0.2%, and phenylephrine 0.5% with cyclopentolate 0.1%, sufficiently dilate preterm infant’s pupil for retinopathy of prematurity eye examinations. These regimens are likely safe for use in preterm infants.